chr1-11996170-A-G

Position:

• chr1-11996170-A-G

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1 PM2 PP2 PP3_Strong PP5_Very_Strong

The NM_014874.4(MFN2):​c.326A>G​(p.Lys109Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. K109K) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MFN2 NM_014874.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 8.95

Genes affected

MFN2 (HGNC:16877): (mitofusin 2) This gene encodes a mitochondrial membrane protein that participates in mitochondrial fusion and contributes to the maintenance and operation of the mitochondrial network. This protein is involved in the regulation of vascular smooth muscle cell proliferation, and it may play a role in the pathophysiology of obesity. Mutations in this gene cause Charcot-Marie-Tooth disease type 2A2, and hereditary motor and sensory neuropathy VI, which are both disorders of the peripheral nervous system. Defects in this gene have also been associated with early-onset stroke. Two transcript variants encoding the same protein have been identified. [provided by RefSeq, Jul 2008]

MFN2 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 17 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain in NM_014874.4
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), MFN2. . Gene score misZ 1.6575 (greater than the threshold 3.09). Trascript score misZ 3.2174 (greater than threshold 3.09). GenCC has associacion of gene with Charcot-Marie-Tooth disease type 2A2, axonal hereditary motor and sensory neuropathy, hereditary motor and sensory neuropathy type 6, Charcot-Marie-Tooth disease, axonal, autosomal recessive, type 2a2b;, multiple symmetric lipomatosis, severe early-onset axonal neuropathy due to MFN2 deficiency.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.969
• PP5: Variant 1-11996170-A-G is Pathogenic according to our data. Variant chr1-11996170-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 476772.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MFN2	NM_014874.4	c.326A>G	p.Lys109Arg	missense_variant	5/19	ENST00000235329.10	NP_055689.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MFN2	ENST00000235329.10	c.326A>G	p.Lys109Arg	missense_variant	5/19	1	NM_014874.4	ENSP00000235329.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Charcot-Marie-Tooth disease type 2A2 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

curation

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Nov 22, 2024

The heterozygous p.Lys109Arg variant in MFN2 was identified by our study in 1 individual with Charcot-Marie-Tooth disease. Trio exome analysis showed this variant to be de novo. The p.Lys109Arg variant in MFN2 has been reported in 3 individuals with Charcot-Marie-Tooth disease (PMID: 31315766, 28660751, 33258288), and was absent from large population studies. This variant has been reported in ClinVar (Variation ID: 476772) and has been interpreted as pathogenic by LabCorp. This variant was found to be de novo in 2 individuals with confirmed paternity and maternity (PMID: 28660751, 31315766). The number of reported affected individuals with this variant is slightly greater than expected compared to non-affected individuals with this variant. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The number of missense variants reported in MFN2 in the general population is lower than expected, suggesting there is little benign variation in this gene and slightly increasing the possibility that a missense variant in this gene may not be tolerated. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for autosomal dominant Charcot-Marie-Tooth disease. ACMG/AMP Criteria applied: PP3_moderate, PS2_moderate, PP2, PM2_supporting, PS4_supporting (Richards 2015). -

Charcot-Marie-Tooth disease type 2 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 27, 2021

This sequence change replaces lysine, a(n) basic and polar amino acid, with arginine, a(n) basic and polar amino acid, at codon 109 of the MFN2 protein (p.Lys109Arg). For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MFN2 protein function. ClinVar contains an entry for this variant (Variation ID: 476772). This missense change has been observed in individual(s) with autosomal dominant Charcot-Marie-Tooth disease (PMID: 28660751, 31315766). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.95	D;D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.93
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	1.0	D;.
M_CAP	Pathogenic	0.73	D
MetaRNN	Pathogenic	0.97	D;D
MetaSVM	Pathogenic	0.93	D
MutationAssessor	Pathogenic	4.1	H;H
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-2.7	D;D
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.96
MutPred		0.77		Loss of ubiquitination at K109 (P = 0.0218);Loss of ubiquitination at K109 (P = 0.0218);
MVP		1.0
MPC		1.6
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.92
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1553142436; hg19: chr1-12056227;